Emil Frei III, M.D., Trailblazer in the Development of Combination Chemotherapy

The pages of medical history are dog-eared with breakthroughs that have transformed medicine and saved lives. One of those dog-eared pages belongs to Emil Frei III, MD, known to his colleagues and friends as Tom. In the dawn of oncology, Dr. Frei, along with his associate, Emil Freireich, MD, did something new in the treatment of cancer—they combined chemotherapies, a transcendent therapeutic approach that accelerated the field and, in turn, saved millions of lives. Dr. Frei died on April 30 at the age of 89.

Emil Frei III was born in St. Louis in 1924 into a free-spirited artistic family. He seemed destined for a life in the arts, but in his early teens, his interests turned toward science, which later seeded his passion to find a cure for cancer. In 1942, he entered St. Louis University as a premed student. A year later, at the onset of WWII, he was drafted into the Navy V-12 college training program. He would attend Colgate University and later, in 1948, graduate from Yale with an MD. After that, he began his internship at the St. Louis University Hospital.

Having been in the V-12 program, Dr. Frei was obligated for active duty, if it became necessary at a later date. “So when Truman sent the troops into Korea, I got a telegram fairly shortly after that. I was in the service for 2 years, 15 months of which were in the Far East and the Korean theater,” said Dr. Frei, during a National Cancer Institute (NCI) Oral History Interview.

After the Korean War, Dr. Frei returned to the St. Louis to finish his residency. One of the professors he conducted research under, Gordon Zubrod, MD, would have a career-changing influence on him. “Dr. Zubrod took a position as the Clinical Director of the NCI and he asked me to join him, which I did in April 1955,” said Dr. Frei.

Soon after arriving at NCI, Dr. Frei met Emil Freireich, MD. Although polar opposites in countenance—Dr. Frei was reserved, cool, contemplative, to Freireich’s intellectual flamboyance—the “two “Emils” would become the closest of associates.

Adventurous Researchers

Backed by a robust Federal government, the NCI was the right place to be for adventurous researchers. Drs. Frei and Freireich had everything they needed: a new clinic, lots of empty beds, a vast laboratory, and the enthusiastic support of the Institute’s Director, Dr. Zubrod. The two researchers decided to focus their clinical activities on acute lymphocytic leukemiaterm (ALL) in children. Asked why they chose leukemia, Dr. Frei said, “There were several reasons. One is that Dr. Jim Holland, who had been there before us, started the program in leukemia, so we inherited his patients, if you will.”

Working on limited scientific “leads” in ALL, Drs. Frei and Freireich attempted to sort out the “chaos in the field” at the time, which was largely a compilation of anecdotes; prospective experimental designs were lacking. At the time, there were two agents—6-mercaptopurine and methotrexate—that showed activity in ALL. At the insistence of Dr. Zubrod, the two young researchers wrote protocols and defined what complete response was in advance, thus defining how to proceed tactically.

It was a watershed event in experimental trial design; however, not without controversy. Dr. Frei explained, “It was controversial because it was felt that we were making patients fit a protocol, whereas you should instead fit the protocol to the patient. It sounds like a compelling argument, but if you don’t really know what you’re doing, you need to have a prospective protocol that asks a question and gets an answer.”

Paradigm Shift in Therapeutics

Within a year, Dr. Frei was named Chief of NCI’s Leukemia Section and later, Chief of Medicine. Frustrated by the short-term remissions achieved in ALL that they were seeing with single-drug therapies, Drs. Frei, Freireich, and Holland began testing combinations of two or more agents to attack the various aspects of leukemia cells’ growth. Testing ideas through controlled experimentation requires a thirst for innovation and change, often in the face of a stubborn status quo. Dr. Frei and his colleagues persevered, marshaling in a paradigm shift in oncology therapeutics: combination chemotherapyterm.

The team also worked on the difficult problem of chemotherapy-related bleeding by demonstrating that the infusion of platelets would allow larger, more effective doses of chemotherapy to be delivered safely.

In 1965, Dr. Frei moved to The University of Texas MD Anderson Cancer Center in Houston, where he served as Associate Director of Clinical Research and Chair of the Department of Experimental Therapeutics. He joined Dana-Farber Cancer Institute in 1972, serving as Physician-in-Chief, succeeding the Institute’s founder, Sidney Farber, MD, who died later that same year. Just 1 year later, Dr. Frei was named Dana-Farber’s Director and Professor of Medicine at Harvard Medical School.

Other Pioneering Work

With Dana-Farber colleagues, Arthur Skarin, MD, and George Canellos, MD, Dr. Frei developed a treatment for adults with non-Hodgkin lymphomaterm, which was one of the first regimens to produce substantial cure rates in the disease. In the 1970s, Dr. Frei’s work helped develop combination therapies that increased survival in breast cancer. During that time, he also participated in pioneering work in the use of bone marrow transplants for a variety of cancers. It is worth noting that under his confident and meticulous stewardship, Dana-Farber became one of the world’s top-rated cancer centers.

In tribute, Dana-Farber President Edward J. Benz, Jr, MD, said, “This approach has led to cures in many patients with cancer. The majority of patients with certain forms of childhood leukemia, Hodgkin disease, testicular cancer, and some other cancers can now expect to live long, high-quality lives because of his contributions.”

Dr. Frei published more than 500 papers in scientific and professional journals and was the recipient of numerous awards and honors. In 1972, he was awarded the Albert Lasker Medical Research Award in recognition of his scientific contributions.

Patients Mattered Most

Even still, in a career as lush with accomplishments, awards, positions, and publications as Dr. Frei’s, it was his patients that mattered most. His work helped bring about the first complete cures for pediatric leukemia patients and led to more effective treatments for adult malignancies ranging from breast cancer to bone cancer. In his early days working in childhood leukemia, when the outcomes were still grim, he remarked, “Children are a challenge, and also a joy to work with.”

That he found joy in caring for desperately ill children is what his colleagues, friends, and patients will best remember him for.

On Monday, February 12, 2007 Senator Dean Heller from Nevada stood on the floor of the U.S. Senate and said, “Madam Speaker, I rise today to pay tribute to Dr. Emil Frei III, a pioneer in cancer treatment, one of the world’s foremost oncologists, and a leader in medical education … His exceptional career deserves the highest commendation and praise.”

I have read with interest the recent tributes to Emil “Tom” Frei III, MD, who passed away in April. I was backstage at the ASCO meetings in 1981, when Dr. Frei was giving his Karnofsky acceptance address. I had a slide presentation at the combined ASCO/AACR session which followed immediately thereafter. Back then, the ASCO and AACR meetings were held during the same week, at the same venue. The ASCO meeting was held on the first 3 days, with the AACR meeting following.

On the afternoon of the final day of the ASCO meeting and on the first day of the AACR meeting, there was a combined ASCO/AACR session, which consisted of about 10 papers felt to be of interest to both ASCO and AACR membership (papers that today would be broadly considered “translational research”). This session followed immediately after the Karnofsky address. I recall the venue as having an actual stage, with a curtained-off waiting area, from where I watched the speech.

Two Types of Researchers

I was thrilled in particular by a portion of Dr. Frei's address, wherein he described two types of clinical cancer researchers, namely "investigators" versus "discoverers." The investigators proceed in a very orderly fashion, are esteemed by their peers, typically succeed (at least in answering the often rather ordinary question being addressed by their work), but produce, at most, single step advances and don't create new paradigms.

Discoverers, on the other hand, follow a path of inquiry which often seems disordered, tend not to be esteemed by their peers, often fail, but, on occasions where they do succeed, produce multi-step advances and create new paradigms. Dr. Frei's point was that the clinical oncology research establishment would be well advised to be more supportive of the work of discoverers.

Since that 1981 speech, the best example of discovery-oriented clinical research since that 1981 speech of which I am aware comes from gastroenterology -- the central role of bacterial infection (helicobactor pylori) in peptic ulcer disease. We've had some breakthroughs of lesser magnitude in oncology: anti-Her2 treatment of breast cancer, anti-CD20 in lymphatic neoplasms, tyrosine kinase inhibitors, etc. When his Karnofsky address was subsequently published in the journal Cancer, there was only passing mention of what had been a major point in the address itself, and this point didn't even appear in the abstract:

[url]http://www.ncbi.nlm.nih.gov/pubmed/7127245

Encouraging Would-be Discoverers

If anyone ever wished to honor Dr. Frei with some type of ASCO award to be presented in his name, it might be, for example, an award for the most creative discovery oriented research presented at the previous year's ASCO meeting. This might focus more attention on the need for more out of the box thinking, in a world where investigators control the peer review pipeline, investigators beget more investigators, and there are decreasing opportunities for would-be discoverers.

Note that the "Emil Frei Award" (1) would be different from the usual awards, which require confirmation through years of follow up work. As Dr. Frei pointed out that discovers often fail, what is honored is a potentially breakthrough idea, supported by credible pilot data.

One important purpose of the award is to focus attention on the new idea, so that it will receive scrutiny and early confirmation or refutation. The fact that the work would attract such scrutiny should serve to discourage fraud and encourage the would be discover to have reasonable certainty that he/she is on a sound path.

Every year, at the International Angiogenesis meeting in LaJolla, they have a whole session devoted to predictive biomarkers. Every year, they conclude that nothing really works.

This brings me back to angiogenesis predictions and the annual LaJolla meetings. For three years in a row, I've presented posters, which show an entirely new way of approaching the problem. I know that it works. It's a breakthrough discovery. But the INVESTIGATORS have no interest whatsoever. The only people who ever came by to look at my posters were fellows in training and the odd weirdo from Southeast Asia or whatever. No one is even curious enough to spend 5 minutes looking at something which is brand new, partly because it's brand new and partly because they don't believe anything which doesn't emanate from the Hallowed Halls of St. Ivory Tower.

I've got two of the posters plus some other stuff posted on the Nature Precedings website. Nature used to do this as a service to people who made discoveries and wanted to just put it up without formal peer review. But they quit doing this a year ago. However, they are maintaining the site. This is brand new, ground breaking stuff. It's real. It's really important. But no one cares, because cancer research has been entirely taken over by INVESTIGATORS who can't see past the end of their nose.

In 2005, Drs. Barry J. Marshall and Robin Warren, both Australians, won the Nobel Prize in medicine for proving, partly by accident, that bacteria and not stress was the main cause of painful ulcers of the stomach and intestine. Yes, a general practioner proved that ulcers are not caused by stress, spicy foods, or even cigarettes and alcohol, but rather by a bacterium. It was one of the most richly deserved Nobel Prizes in Medicine ever awarded.

Prior to the discovery, the number one surgical operation (in terms of revenue produced for the surgeons and hospitals) was the vagotomy and antrectomy. Prior to the discovery, the number one drugs were H2 receptor blockers like Tagamet and the then up and coming proton pump inhibitors like omeprazole. Single handedly, he got rid of both the number one surgical operation and the largest part of the market for the number one drugs, dealing a huge blow to both big surgery and big pharma, and making the lives of tens of millions much more pain free and enjoyable.

How many loved-ones had died of a bleeding ulcer? Today, they would have been cured permanently by a two week course of antibiotics. Oh! How having that big mug of thick black coffee without having to chase it with a half bottle of Maalox!

And the Aussie did it without any research grants and over the dead body opposition of the entire world of medicine, gastroenterology, surgery, the NIH, and the pharmaceutical industry. And, for gosh sakes, he used himself as the definitive guinea pig!

In 1982, Dana Farber's Emil Frey won the Karnofsky Award. In his acceptance speech at ASCO, he decried the demise of the "discoverer" (risk taker, not so well organized, high failure rate, but big payoff when successful) because of the ascendancy of the "investigator" culture (no risk taking, well organized, exhaustive analysis of trivial hypotheses, huge payoff when successful).

The mindset of rewarding academic achievement and publication over all else. We would all like to think that organizations, government agencies, scientists, researchers, and even practitioners work together, sharing information "for the benefit of patients." However, each group has its own priorities and its own agenda. Moreover, the image of cooperation between these very different groups only gives the illusion that reform isn't needed. The present system exists to serve academic achievement and publication, but not to serve the best interests of people.

This is a perfect example of thirty-five years of the trial-and-error mind-set (empiricism) that has occupied cancer research. The cancer "investigator" culture that prizes itself on the exhaustive examination of trivial hypotheses, while eschewing support of cancer "discoverer" type research, attempting to create entirely new paradigms of cancer treatment. A dysfunctional culture that pushes tens of thousands of physicians and scientists toward the goal of finding the tiniest improvements in treatment rather than genuine breakthroughs, that rewards academic achievment and publication even though their proven "activity" has little to do with curing cancer.

If you ever get a chance to watch a 1940 movie, starring Edward G Robinson, called "Dr. Ehrlich's Magic Bullet," watch it. Ehrlich is one of the very first pioneers of chemotherapy. Ehrlich was the discoverer of the first effective treatment for syphillis. The movie is a very accurate foreshadowing of chemotherapy of cancer, one century later. Ehrlich's treatment was very toxic, but it worked, sometimes miraculously. This work inspired Alexander Fleming, who later discovered penicillin, which was a true magic bullet (Ehrlich's bullet was a wondrous bullet, but it wasn't magic).

The belief that research grants and the NIH will be our salvation can be so off base. Here and there around the world, there are decisions still being made by folks who aren't in the pockets of American Big Business. Individual intelligence, integrity and curiosity. Maybe there is a glimmer of hope?

Advances in cancer therapy increasingly reflect the application of genomics and proteomics to target tumor-specific phenomena. Several insights have accelerated this process including the primacy cell survival signals in carcinogenesis and drug resistance and the growing appreciation of tumor biology as contextual.

Cell function analysis of programmed cell death addresses both issues by measuring metabolic and morphologic features of drug induced cell death (apoptotic and non-apoptotic) using native cultures isolated from surgical specimens and cytologically + fluids. The predictive validity of this functional profiling platform established for cytotoxics, has led to this platforms current focus on signal transduction. A cell "function" exploration of "vertical" and "horizontal" signal inhibition.

By expanding beyond current FDA-approved drugs into the new agents that target PI3K, AKT, TORC1&2, MEK/ERK and c-MET, functional profiling can facilitate developmental therapeutics. Analyses are now examining the activity and synergy of EGFR-TKIs with VEGF, mTOR, MEK/ERK, PI3K, AKT and c-MET inhibitors in various diseases.

There are lots of things that determine if drugs work, beyond the existence of a given target. Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can't be predicted on the basis of static gene expression patterns?

There are a number of drugs that could hold benefit for the patient with ovarian cancer and a number of novel combinations. Drugs are tested for activity both as single agents and in rational drug combinations, in order to assess possible drug synergies.

This involves using functional profiling analysis that allows for simultaneous identification of anti-tumor activity and anti-vascular activity in established anti-cancer drug treatments and also in novel combinations of standard drugs, kinase-inhibiting drugs and anti-angiogenesis agents.

The New York Yankees catcher Yogi Berra famous quote, “Déjà vu all over again,” reminds me of the growing focus on the concept of “N- of-1.” For those of you unfamiliar with the catchphrase, it refers to a clinical trial of one subject.

In clinical research, studies are deemed reportable when they achieve statistical significance. The so-called power analysis is the purview of the biostatistician who examines the desired outcome and explores the number of patients (subjects) required to achieve significance. The term “N” is this number. The most famous clinical trials are those large, cooperative group studies that, when successful, are considered practice-changing. That is, a new paradigm for a disease is described. To achieve this level of significance it is generally necessary to accrue hundreds, even thousands of patients. This is the “N” that satisfies the power analysis and fulfills the investigators expectations.

So what about an N-of-1? This disrupts every tenet of cancer research, upends every power analysis, and completely rewrites the book of developmental therapeutics. Every patient is his or her own control. Their good outcome reflects the success or failure of “the trial.” There is no power analysis. It is an “N” of 1.

This “breakthrough” concept however, has been the underpinning of the work of investigators like Drs. Larry Weisenthal, Andrew Bosanquet, Ian Cree, myself and all the other dedicated researchers who pioneered the concept of advancing cancer outcomes one patient at a time. These intrepid scientists described the use of each patient’s tissue to guide therapy selection. They wrote papers, conducted trials and reported their successful results in the peer-reviewed literature. These results I might add have provided statistically significant improvements in clinical responses, times to progression, even survival. By incorporating the contribution of the cellular milieu into clinical response prediction, these functional platforms have consistently outperformed their genomic counterparts in therapy selection So why, one might ask, have the efforts of these dedicated investigators fallen on deaf ears?

I think that the explanation lies in the fact that we live in a technocracy. In this environment, science has replaced religion and medical doctors have abdicated control of clinical development to the basic scientists and basic scientists love genomics. It is no longer enough to have good results; you have to get the results the right way. And so, meaningful advances in therapeutics based on functional platforms have been passed over in favor of marginal advances based on genomic platforms.

There is nothing new about N-of-1. It has been the subject of these investigators compelling observations for more than two decades. Though functional platforms are not perfect, they provide a 2.04 (1.62 to 2.57, P < 0.001) fold improvement in clinical response for virtually all forms of cancer – as we will be reporting (Apfel C, et al Proc ASCO, 2013).

It seems that in the field of cancer therapeutics “perfect is the enemy of good.” By this reasoning, good tests should not be used until perfect tests are available. Unfortunately, for the thousands of Americans who confront cancer each day there are no perfect tests. Perhaps we should be more willing to use good ones while we await the arrival of perfect ones. After all, it was Yogi Berra who said, “If the world was perfect, it wouldn’t be.”

Anyone patient cured of metastatic cancer has been cured by combination chemotherapy

Combination chemotherapy is harsh. The drugs are poisons. Side effects can be severe. Nausea and vomiting, while better controlled today, remain a problem. Weakness, fatigue, low white blood cell counts, infections, hair loss, and nerve damage, the list is long.

There are also significant long-term problems, including heart disease, brain dysfunction, hearing loss and the development of new cancers. Most anticancer drugs are carcinogenic. Nonetheless, the fact remains that almost every person that has ever been cured of metastatic cancer has been cured by "combination" chemotherapy (a small number of patients have been cured by immunotherapy). The approach has proven successful in a wide range of cancers (Frei E. et al, Cancer Res. 1985 Dec;45:6523-37).

The problem is that combination chemotherapy has run into a brick wall. It has not proven possible to extend the success of combination chemotherapy in childhood cancers, leukemia, lymphoma, and testicular cancer to cancer in general. The common metastatic cancers such as breast, lung, colon, prostate, bladder, kidney, melanoma, ovarian, and pancreatic have resisted cure by combination chemotherapy.

It is not that there has been no progress, but it has been painfully slow and limited. All too often patients and their physicians are confronted with the depressing task of balancing the severe side effects of chemotherapy and their negative impact on the quality of life against potential survival benefits.

The second reason that cure has been largely abandoned as a research goal is the complexity of the disease. What previously had been hidden is now exposed to plain view. We can now look inside the black box of the cancer cells. What we see is chaos. Every cell is different, and the cancer cells keep changing, even in the same patient.

The problem is tumor cell evolution. To achieve cure, therapy must address the problem of tumor cell evolution. Cancer can be cured. This is a fact. Thousands of patients are alive today, cured of metastatic cancer.

In 1985 Dr. Frei wrote: "To the extent that physicians and investigators are ambivalent with respect to the term 'cure,' patients and the medical community will be skeptical. One of the obstacles to progress in cancer therapy generally and in cancer chemotherapy specifically has been the presence of such skepticism" (Frei E. et al, Cancer Res. 1985 Dec;45:6523-37).

This report, shown at the American Society of Clinical Oncology trade show of 2013, showed a 2.02 higher response rate (P < 0.001) and a 1.44 improvement in one year survival (P < 0.02) for patients who received assay-guided therapy. This established the predicative validity of the functional profiling approach.

Accuracy and clinical utility of in vitro cytometric profiling to personalize chemotherapy: Preliminary findings of a systematic review and meta-analysis.

Cytometric analysis, or in-vitro functional profiling, has been developed as a method to predict tumor response to different drugs with the premise to personalize chemotherapy and improve patient outcomes.

Methods:

We performed a systematic review and a meta-analysis a) of correlative studies using cytometric profiling that reported diagnostic accuracy (sensitivity and specificity) and b) of effectiveness studies comparing patient outcomes when allocated to treatment guided by a cytometric assay versus population-based standard of care. We used Meta-DiSc software to find pooled sensitivity and specificity and analyze the summary receiver operating characteristic (sROC) curve and used Review Manager 5.1 to generate forest plots on overall tumor response (50% or greater decrease in tumor diameter) and on 1-year overall survival.

Despite various limitations of individual studies, the aggregate and fairly consistent evidence of these data suggests cytometric profiling to be accurate, to improve overall tumor response, and to increase 1-year patient survival. Given the enormous potential for our society, a well-designed and sufficiently-powered randomized controlled trial is urgently needed to validate these results.

Personalized oncology has advanced through genomic and proteomic platforms. BCR-abl; EGFr and ALK have provided drug-able targets and companion diagnostics in several diseases, yet many transforming events in humans are polygenic, complex and incompletely understood at a genomic level. Recognition that oncogenesis reflects changes in the cell and its micro environment has renewed interest in whole cell experimental models that capture native-state cell-cell, -stroma and -vascular signaling. Ex vivo analysis of programmed cell death (EVA/PCD) has been shown to correlate significantly with response, time to progression and survival (Nagourney, R. Curr. Treat Op Oncol, 2006).To explore EVA/PCD functional profiling in Brazil, hospital-based investigators, Centro de Genomas and Rational Therapeutics coordinated the transport of 67 surgical specimens for analyses.

Methods:

Dose-response curves using metabolic (ATP-content, mitochondrial) and morphologic endpoints, interpolated to LC50's and synergy by median-effect, were compared with databases to identify patient-specific profiles for cytotoxics, targeted agents and combinations. Reports provided day 7.